Unsubstituted and substituted 4-benzyl-1,3-dihydro-imidazole-2-thiones acting as specific or selective alpha2 adrenergic agonists and methods for using the same

ABSTRACT

Compounds of Formula 1 
     
       
         
         
             
             
         
       
     
     where the variables have the meaning defined in the specification are used to activate alpha 2  adrenergic receptors. The compounds of Formula 1 are incorporated in pharmaceutical compositions and are used as medicaments in mammals, including humans, for treatment of diseases and or alleviations of conditions which are responsive to treatment by agonists of alpha 2  adrenergic receptors.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Divisional of U.S. patent application Ser. No.11/232,287, filed Sep. 20, 2005, which claims the benefit of U.S.provisional patent application Ser. No. 60/613,870, filed 28 Sep. 2004,each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to methods of using unsubstituted andsubstituted 4-benzyl-1,3-dihydro-imidazole-2-thiones as agonists ofalpha 2 adrenergic receptors in mammals, and to certain novel compoundsof the same general structure. The present invention also relates topharmaceutical compositions containing one or more compounds having theunsubstituted and substituted 4-benzyl-1,3-dihydro-imidazole-2-thionestructure as active ingredient for modulating the alpha₂ adrenergicreceptors in mammals, and even more specifically for utilizing thesecompounds and pharmaceutical compositions to alleviate chronic pain,allodynia, muscle spasticity, diarrhea, neuropathic pain, visceral painand other diseases and conditions.

BACKGROUND ART

Human adrenergic receptors are integral membrane proteins which havebeen classified into two broad classes, the alpha and the betaadrenergic receptors. Both types mediate the action of the peripheralsympathetic nervous system upon binding of catecholamines,norepinephrine and epinephrine.

Norepinephrine is produced by adrenergic nerve endings, whileepinephrine is produced by the adrenal medulla. The binding affinity ofadrenergic receptors for these compounds forms one basis of theclassification: alpha receptors tend to bind norepinephrine morestrongly than epinephrine and much more strongly than the syntheticcompound isoproterenol. The preferred binding affinity of these hormonesis reversed for the beta receptors. In many tissues, the functionalresponses, such as smooth muscle contraction, induced by alpha receptoractivation are opposed to responses induced by beta receptor binding.

Subsequently, the functional distinction between alpha and betareceptors was further highlighted and refined by the pharmacologicalcharacterization of these receptors from various animal and tissuesources. As a result, alpha and beta adrenergic receptors were furthersubdivided into α₁, α₂, β₁, and β₂ subtypes. Functional differencesbetween α₁ and α₂ receptors have been recognized, and compounds whichexhibit selective binding between these two subtypes have beendeveloped. Thus, in published international patent application WO92/0073, the selective ability of the R(+) enantiomer of terazosin toselectively bind to adrenergic receptors of the α₁ subtype was reported.The α₁/α₂ selectivity of this compound was disclosed as beingsignificant because agonist stimulation of the α₂ receptors was said toinhibit secretion of epinephrine and norepinephrine, while antagonism ofthe α₂ receptor was said to increase secretion of these hormones. Thus,the use of non-selective alpha-adrenergic blockers, such asphenoxybenzamine and phentolamine, was said to be limited by their α₂adrenergic receptor mediated induction of increased plasma catecholamineconcentration and the attendant physiological sequelae (increased heartrate and smooth muscle contraction).

For a further general background on the α-adrenergic receptors, thereader's attention is directed to Robert R. Ruffolo, Jr.,α-Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology,(Progress in Basic and Clinical Pharmacology series, Karger, 1991),wherein the basis of α₁/α₂ subclassification, the molecular biology,signal transduction, agonist structure-activity relationships, receptorfunctions, and therapeutic applications for compounds exhibitingα-adrenergic receptor affinity is explored.

The cloning, sequencing and expression of alpha receptor subtypes fromanimal tissues has led to the subclassification of the α₁adrenoreceptors into α_(1A), α_(1B), and α_(1D). Similarly, the α₂adrenoreceptors have also been classified α_(2A), α_(2B), and α_(2C)receptors. Each α₂ receptor subtype appears to exhibit its ownpharmacological and tissue specificities. Compounds having a degree ofspecificity for one or more of these subtypes may be more specifictherapeutic agents for a given indication than an α₂ receptorpan-agonist (such as the drug clonidine) or a pan-antagonist.

Among other indications, such as the treatment of glaucoma,hypertension, sexual dysfunction, and depression, certain compoundshaving alpha₂ adrenergic receptor agonist activity are known analgesics.However, many compounds having such activity do not provide the activityand specificity desirable when treating disorders modulated by alpha₂adrenoreceptors. For example, many compounds found to be effectiveagents in the treatment of pain are frequently found to have undesirableside effects, such as causing hypotension and sedation at systemicallyeffective doses. There is a need for new drugs that provide relief frompain without causing these undesirable side effects. Additionally, thereis a need for agents which display activity against pain, particularlychronic pain, such as chronic neuropathic and visceral pain.

U.S. Pat. No. 4,798,843 describes (phenyl)-imidazole-2-thiones andsubstituted (phenyl)-imidazole-2-thiones which are used as dopamine Bhydroxylase inhibitors.

PCT Publication WO 03/099795 published on Dec. 4, 2003 describes4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substitutedcycloalkenylmethyl) imidazole-2-thiones and related compounds and theiruse as specific or selective agonists of alpha_(2B) and/or alpha_(2C)adrenergic receptors.

PCT Publication WO 02/36162 published on May 10, 2002 discloses somecyloalkenyl-methyl-imidazoles, condensed cyclic-methyl imadazoles and animidazole thione of the following structure

as an alpha_(2B) or alpha_(2C) selective agonist utilized for treatmentof ocular neovascularization.

British Patent 1 499 485, published Feb. 1, 1978 describes certainthiocarbamide derivatives; some of these are said to be useful in thetreatment of conditions such as hypertension, depression or pain.

PCT Publications WO01/00586 published on Jan. 4, 2001 and WO99/28300published on Jun. 10, 1999 describe certain imidazole derivatives actingas agonists of alpha_(2B) and/or alpha_(2C) adrenergic receptors. U.S.Pat. No. 6,313,172 discloses phenylmethyl-thiourea derivatives used fortreatment of pain.

U.S. Pat. Nos. 6,545,182 and 6,313,172 describephenylmethyl-(2-hydroxy)ethylthioureas which have no significantcardiovascular or sedative effects and are useful for alleviatingchronic pain and allodynia. U.S. Pat. No. 6,534,542 describescycloalkyl, cycloalkenyl, cycloalkylmethyl and cycloalkenylmethyl(2-hydroxy)ethylthioureas and their use as specific or selectiveagonists of alpha_(2B) adrenergic receptors.

As further background to the present invention the compounds of U.S.Pat. Nos. 6,124,330 and 6,486,187 are mentioned. These compounds aresaid to have retinoic mimetic activity.

SUMMARY OF THE INVENTION

The present invention is directed to methods of activating alpha₂adrenergic receptors in mammals using the compounds of Formula 1

where n is an integer having the values of 0 to 5;R₁ is independently selected from the group consisting of alkyl of 1 to4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons,(CH₂)_(m)OR₂, (CH₂)_(m)NR₃R₄, (CH₂)_(m)CN, C(O)R₅, C(O)OR₅,(CH₂)_(m)SO₂R₅, aryl, heteroaryl, F, Cl, Br, I, fluoroalkyl containing 1to 4 carbon atoms and 1 to 9 fluoro atoms, fluoroalkoxy containing 1 to4 carbon atoms and 1 to 9 fluoro atoms, N₃ and NO₂, said heteroarylhaving 1 to 3 heteroatoms independently selected from O, N and S, andsaid aryl and heteroaryl groups being optionally substituted with 1 to 3radicals selected from the group consisting of alkyl of 1 to 4 carbons,alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, (CH₂)_(m)OR₂,(CH₂)_(m)NR₃R₄, (CH₂)_(m)CN, C(O)R₅, C(O)OR₅, (CH₂)_(m)SO₂R₅,fluoroalkyl containing 1 to 4 carbon atoms and 1 to 9 fluoro atoms,fluoroalkoxy containing 1 to 4 carbon atoms and 1 to 9 fluoro atoms, N₃and NO₂,m is an integer having the values of 0, 1, 2, or 3;R₂ is H, alkyl of 1 to 4 carbons, C(O)R₅, and aryl, or heteroarylcontaining 1 to 3 heteroatoms independently selected from O, N and S,and said aryl and heteroaryl groups being optionally substituted with 1to 3 radicals selected from the group consisting of alkyl of 1 to 4carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons,(CH₂)_(m)OR₂, (CH₂)_(m)NR₃R₄, (CH₂)_(m)CN, C(O)R₅, C(O)OR₅,(CH₂)_(m)SO₂R₅, fluoroalkyl containing 1 to 4 carbon atoms and 1 to 9fluoro atoms, fluoroalkoxy containing 1 to 4 carbon atoms and 1 to 9fluoro atoms, N₃ and NO₂;R₃ and R₄ are independently selected from the group consisting of H,alkyl of 1 to 4 carbons, C(O)R₅ and benzyl;R₅ is independently H, alkyl of 1 to 4 carbons, aryl, or heteroarylcontaining 1 to 3 heteroatoms independently selected from O, N and S,and said aryl and heteroaryl groups being optionally substituted with 1to 3 radicals selected from the group consisting of alkyl of 1 to 4carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons,(CH₂)_(m)OR₂, (CH₂)_(m)NR₃R₄, (CH₂)_(m)CN, C(O)R₅, C(O)OR₅,(CH₂)_(m)SO₂R₅, fluoroalkyl containing 1 to 4 carbon atoms and 1 to 9fluoro atoms, fluoroalkoxy containing 1 to 4 carbon atoms and 1 to 9fluoro atoms, N₃ and NO₂.

The present invention also includes novel compounds having the formulas

In another aspect the present invention is directed to pharmaceuticalcompositions containing as the active ingredient one or more compoundsof Formula 1, and or one or more of the novel compounds shown above, thecompositions being utilized as medicaments in mammals, including humans,for treatment of diseases and or alleviations of conditions which areresponsive to treatment by agonists of alpha₂ adrenergic receptors. Thecompositions containing the compounds of the invention are primarily,but not exclusively, used for alleviation of chronic pain and/orallodynia. Some of the compounds used in the methods of the inventionhave the demonstrable advantageous property that they are specific orselective to alpha_(2B) and/or alpha_(2C) adrenergic receptors inpreference over alpha_(2A) adrenergic receptors, and some compounds haveno or only minimal cardivascular and/or sedatory activity.

DETAILED DESCRIPTION OF THE INVENTION

A general description of the compounds used in the methods of theinvention is provided in the Summary section of the present applicationfor patent with reference to Formula 1. It will be readily apparent tothose skilled in the art that some of the compounds depicted in Formula1 may exist in trans (E) and cis (Z) isomeric forms. Moreover, some ofthe compounds of the invention may contain one or more asymmetriccenters, such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all trans (E) and cis (Z)isomers, enantiomers, diastereomers and racemic mixtures. Some of thecompounds of the invention may form salts with pharmaceuticallyacceptable acid or base, and methods using such pharmaceuticallyacceptable salts of the compounds of Formula 1 are also within the scopeof the invention.

The imidazole-2-thione compounds of the present invention can undergotautomeric transformations and can be depicted by the tautomericformulas shown below. All tautomers of Formula 1 are within the scope ofthe invention.

Generally speaking and referring to Formula 1, in the compoundspreferably used in the methods of treatment of the present invention

The variable R₁ is preferably halogen, even more preferably F, Cl, Br,—CH₃, CH₂CH₃, —CF₃, —CH₂OH preferably at the position(s) ortho and ormeta to the bridge;n is preferably 1 or 2;m is preferably 1;R₂ is preferably H;R₃ and R₄ is preferably H or Me, andR₅ is preferably H, or Me.The presently most preferred compounds used in the methods of treatmentof the present invention are the novel compounds 1 to 5.

General Methods for Obtaining the Compounds of the Invention

Reaction Schemes A-B illustrate illustrate general methods for obtainingthe 4-(benzyl-1,3-dihydro)-imidazole-2-thiones).

Reaction Scheme A employs an alpha-halo ketone of Formula 2 which can beobtained through commercial sources or prepared in accordance with knownprocedures in the chemical scientific and patent literature or by suchmodifications of known procedures which are readily apparent to thepracticing synthetic organic chemist. The variables R₁ and n are definedas in connection with Formula 1. The compound of Formula 2 is reactedwith formamide to provide the imidazole compounds of Formula 3. Theimidazoles of Formula 3 are reacted with phenyl chlorothionoformate inthe presence of sodium bicarbonate and water and subsequently treatedwith a base, such as triethylamine to produce4-((benzyl-1,3-dihydro)-imidazole-2-thiones) of Formula 1.

Reaction Scheme B employs an aldehyde starting material of Formula 4which can be obtained through commercial sources or prepared inaccordance with known procedures in the chemical scientific and patentliterature or by such modifications of known procedures which arereadily apparent to the practicing synthetic organic chemist. Thealdehyde of Formula 4 is reacted with tosyl methylisocyanide (TosMIC)and sodium cyanide and thereafter heated in the presence of excessammonia to produce the imidazole compounds of Formula 3. The imidazolesof Formula 3 are reacted with phenyl chlorothionoformate as describedabove to obtain compounds of Formula 1.

Reaction Scheme C provides a general method for preparing compounds ofFormula 1. The variables in Reaction Scheme C are defined in the samemanner as in connection with Formula 1. An aldehyde of Formula 5 is thestarting material which can be obtained through commercial sources orprepared in accordance with known procedures in the chemical scientificand patent literature or by modifications of known procedures which arereadily apparent to the practicing synthetic organic chemist. Thealdehyde Formula 5 is reacted with a Grignard reagent of4-iodo-1-triphenylmethyl-1H-imidazole to provide the triphenylmethyl(trityl) protected hydroxyimidazole compounds of Formula 6.Deoxygenation of the bridging hydroxyl moiety was accomplished bymethods such as treatment with trifluoroacetic acid (TFA) in triethylsilane (Et₃SiH), followed by acidic deprotection of the trityl group toproduce imidazoles of Formula 3. The imidazoles of Formula 3 are reactedwith phenyl chlorothionoformate in the presence of sodium bicarbonateand water and subsequently treated with a base, such as triethylamine toproduce 4-benzyl-1,3-dihydro-imidazole-2-thiones of Formula 1. Thecompounds of Formula 1 are within the scope of the present invention.

The synthesis of the novel compounds of the present invention isdescribed in the Experimental section of the present application.

Biological Activity, Modes of Administration

The imidazole-2-thione compounds of Formula 1 and the novel compounds 1through 5 are used in accordance with the present invention as agonistsof alpha₂ adrenergic receptors. Some compounds of Formula 1 may act asspecific or selective agonists of alpha_(2B) and/or to alpha_(2C)adrenergic receptors, in preference over alpha_(2A) adrenergicreceptors. The novel Compounds 3, 4 and 5 are specific agonists ofalpha_(2B) agonists in preference over alpha_(2A) and alpha_(2C)adrenergic receptors. The specific or selective activity of thecompounds of Formula 1 in general and of the novel compounds of theinvention can be tested in an assay titled Receptor Selection andAmplification technology (RSAT) assay, which is described in thepublication by Messier et. Al., 1995, Pharmacol. Toxicol. 76, pp.308-311 (incorporated herein by reference) and is also described below.Another reference pertinent to this assay is Conklin et al. (1993)Nature 363:274-6, Receptor Selection and Amplification Technology (RSAT)assay, also incorporated herein by reference.

The RSAT assay measures a receptor-mediated loss of contact inhibitionthat results in selective proliferation of receptor-containing cells ina mixed population of confluent cells. The increase in cell number isassessed with an appropriate transfected marker gene such asbeta-galactosidase, the activity of which can be easily measured in a96-well format. Receptors that activate the G protein, G_(q), elicitthis response. Alpha₂ receptors, which normally couple to G_(i),activate the RSAT response when coexpressed with a hybrid Gq proteinthat has a Gi receptor recognition domain, called Gq/i5.

NIH-3T3 cells are plated at a density of 2×10⁶ cells in 15 cm dishes andmaintained in Dulbecco's modified Eagle's medium supplemented with 10%calf serum. One day later, cells are cotransfected by calcium phosphateprecipitation with mammalian expression plasmids encodingp-SV-beta-galactosidase (5-10 μg), receptor (1-2 μg) and G protein (1-2μg). 40 μg salmon sperm DNA may also be included in the transfectionmixture. Fresh media is added on the following day and 1-2 days later,cells are harvested and frozen in 50 assay aliquots. Cells are thawedand 100 μl added to 100 μl aliquots of various concentrations of drugsin triplicate in 96-well dishes. Incubations continue 72-96 hr at 37° C.After washing with phosphate-buffered saline, beta-galactosidase enzymeactivity is determined by adding 200 μl of the chromogenic substrate(consisting of 3.5 mM o-nitrophenyl-beta-D-galactopyranoside and 0.5%nonidet P-40 in phosphate buffered saline), incubating overnight at 30°C. and measuring optical density at 420 nm. The absorbance is a measureof enzyme activity, which depends on cell number and reflects areceptor-mediated cell proliferation. The efficacy or intrinsic activityis calculated as a ratio of the maximal effect of the drug to themaximal effect of a standard full agonist for each receptor subtype.Brimonidine, also called UK14304, the chemical structure of which isshown below, is used as the standard agonist for the alpha_(2A),alpha_(2B) and alpha_(2C) receptors.

Results of the RSAT assay for the novel compounds of the invention areshown in Table 1 below.

Biological Data : Intrinsic Activity Alpha Alpha Alpha Structure 2A 2B2C

0.74 1.11 1.18 Compound 1

0.78 1.05 NA Compound 2

NA 1.3 NA Compound 3

NA 0.92 NA Compound 4

NA 0.95 NA Compound 5

NA 0.70 0.71 Compound 6NA stands for “not active” at concentrations less than 10 micromolar.Diseases that may be treated in accordance with this invention,generally speaking with compounds of Formula 1 and specifically with thenovel compounds 1 through 5 include, but are not limited toneurodegenerative aspects of the following conditions:MACULOPATHIES/RETINAL DEGENERATION Non-Exudative Age Related MacularDegeneration (ARMD), Exudative Age Related Macular Degeneration (ARMD),Choroidal Neovascularization, Diabetic Retinopathy, Central SerousChorioretinopathy, Cystoid Macular Edema, Diabetic Macular Edema, MyopicRetinal Degeneration,UVEITIS/RETINITIS/CHOROIDITIS/OTHER INFLAMMATORY DISEASES AcuteMultifocal Placoid Pigment Epitheliopathy, Behcet's Disease, BirdshotRetinochoroidopathy, Infectious (Syphilis, Lyme, Tuberculosis,Toxoplasmosis), Intermediate Uveitis (Pars Planitis), MultifocalChoroiditis, Multiple Evanescent White Dot Syndrome (MEWDS), OcularSarcoidosis, Posterior Scleritis, Serpiginous Choroiditis, SubretinalFibrosis and Uveitis Syndrome, Vogt-Koyanagi-Harada Syndrome, PunctateInner Choroidopathy, Acute Posterior Multifocal Placoid PigmentEpitheliopathy, Acute Retinal Pigement Epitheliitis, Acute MacularNeuroretinopathyVASUCLAR DISEASES/EXUDATIVE DISEASES Diabetic retinopathy, RetinalArterial Occlusive Disease, Central Retinal Vein Occlusion, DisseminatedIntravascular Coagulopathy, Branch Retinal Vein Occlusion, HypertensiveFundus Changes, Ocular Ischemic Syndrome, Retinal ArterialMicroaneurysms, Coat's Disease, Parafoveal Telangiectasis, Hemi-RetinalVein Occlusion, Papillophlebitis, Central Retinal Artery Occlusion,Branch Retinal Artery Occlusion, Carotid Artery Disease (CAD), FrostedBranch Angiitis, Sickle Cell Retinopathy and other Hemoglobinopathies,Angioid Streaks, Familial Exudative Vitreoretinopathy, Eales Disease

TRAUMATIC/SURGICAL/ENVIRONMENTAL Sympathetic Ophthalmia, Uveitic RetinalDisease, Retinal Detachment, Trauma, Laser, PDT, Photocoagulation,Hypoperfusion During Surgery, Radiation Retinopathy, Bone MarrowTransplant Retinopathy PROLIFERATIVE DISORDERS Proliferative VitrealRetinopathy and Epiretinal Membranes

INFECTIOUS DISORDERS Ocular Histoplasmosis, Ocular Toxocariasis,Presumed Ocular Histoplasmosis Syndrome (POHS), Endophthalmitis,Toxoplasmosis, Retinal Diseases Associated with HIV Infection, ChoroidalDisease Associate with HIV Infection, Uveitic Disease Associate with HIVInfection, Viral Retinitis, Acute Retinal Necrosis, Progressive OuterRetinal Necrosis, Fungal Retinal Diseases, Ocular Syphilis, OcularTuberculosis, Diffuse Unilateral Subacute Neuroretinitis, MyiasisGENETIC DISORDERS Retinitis Pigmentosa, Systemic Disorders withAccosiated Retinal Dystrophies, Congenital Stationary Night Blindness,Cone Dystrophies, Stargardt's Disease And Fundus Flavimaculatus, Best'sDisease, Pattern Dystrophy of the Retinal Pigmented Epithelium, X-LinkedRetinoschisis, Sorsby's Fundus Dystrophy, Benign Concentric Maculopathy,Bietti's Crystalline Dystrophy, pseudoxanthoma elasticum

RETINAL TEARS/HOLES Retinal Detachment, Macular Hole, Giant Retinal Tear

TUMORS Retinal Disease Associated With Tumors, Congenital Hypertrophy OfThe RPE, Posterior Uveal Melanoma, Choroidal Hemangioma, ChoroidalOsteoma, Choroidal Metastasis, Combined Hamartoma of the Retina andRetinal Pigmented Epithelium, Retinoblastoma, Vasoproliferative Tumorsof the Ocular Fundus, Retinal Astrocytoma, Intraocular Lymphoid Tumors.

Generally speaking alpha₂ agonists, can alleviatesympathetically-sensitized conditions that are typically associated withperiods of stress. These include the neurological conditions of 1)increased sensitivity to stimuli such as intracranial pressure, lightand noise characteristic of migraines and other headaches; 2) theincreased sensitivity to colonic stimuli characteristic of IrritableBowel Syndrome and other GI disorders such as functional dyspepsia; 3)the sensation of itch associated with psoriasis and other dermatologicalconditions; 4) muscle tightness and spasticity; 5) sensitivity tonormally innocuous stimuli such as light touch and spontaneous paincharacteristic of conditions like fibromyalgia; 6) variouscardiovascular disorders involving hypertension, tachycardia, cardiacischemia and peripheral vasoconstriction; 7) metabolic disordersincluding obesity and insulin resistance; 8) behavioral disorders suchas drug and alcohol dependence, obsessive-compulsive disorder,Tourette's syndrome, attention deficit disorder, anxiety and depression;9) altered function of the immune system such as autoimmune diseasesincluding lupus erythematosis and dry eye disorders; 10) chronicinflammatory disorders such as Crohn's disease and gastritis; 11)sweating (hyperhydrosis) and shivering; and 12) sexual dysfunction.

Alpha₂ agonists including alpha_(2B/2C) agonists are also useful in thetreatment of glaucoma, elevated intraocular pressure, neurodegenerativediseases including Alzheimer's, Parkinsons, ALS, schizophrenia, ischemicnerve injury such as stroke or spinal injury, and retinal injury asoccurs in glaucoma, macular degeneration, diabetic retinopathy, retinaldystrophies, Lebers optic neuropathy, other optic neuropathies, opticneuritis often associated with multiple sclerosis, retinal veinocclusions, and following procedures such as photodynamic therapy andLASIX. Also included are chronic pain conditions such as cancer pain,post-operative pain, allodynic pain, neuropathic pain, CRPS orcausalgia, visceral pain.

A compound is considered selective agonist of alpha_(2B) and/oralpha_(2C) adrenergic receptors in preference over alpha_(2A) receptors,if the compound is more active, preferably at least ten (10) times moreactive towards either alpha_(2B) or towards alpha_(2C) receptors thantowards alpha_(2A) receptors. It can be seen from these tables that manycompounds of the invention are specific or selective agonists ofalpha_(2B) and/or alpha_(2C) adrenergic receptors within the formerdefinition, and in fact have no agonist like activity or onlyinsignificant agonist-like activity on alpha_(2A) receptors. Thus, theimidazole-2-thione compounds are used in accordance with the presentinvention for treating conditions and diseases which are responsive totreatment by alpha₂ including alpha_(2B) and/or alpha_(2C) adrenergicagonists. Such conditions and diseases include, but are not limited to,pain including chronic pain (which may be, without limitation visceral,inflammatory, referred or neuropathic in origin) neuropathic pain,corneal pain, glaucoma, reducing elevated intraocular pressure, ischemicneuropathies and other neurodegenerative diseases, diarrhea, and nasalcongestion. Chronic pain may arise as a result of, or be attendant to,conditions including without limitation: arthritis, (includingrheumatoid arthritis), spondylitis, gouty arthritis, osteoarthritis,juvenile arthritis, and autoimmune diseases including withoutlimitation, lupus erythematosus. Visceral pain may include, withoutlimitation, pain caused by cancer or attendant to the treatment ofcancer as, for example, by chemotherapy or radiation therapy. Inaddition, the compounds of this invention are useful for treating musclespasticity including hyperactive micturition, diuresis, withdrawalsyndromes, neurodegenerative diseases including optic neuropathy, spinalischemia and stroke, memory and cognition deficits, attention deficitdisorder, psychoses including manic disorders, anxiety, depression,hypertension, congestive heart failure, cardiac ischemia and nasalcongestion, chronic gastrointestinal inflammations, Crohn's disease,gastritis, irritable bowel disease (IBD), functional dyspepsia andulcerative colitis. The activity of the alpha_(2B/2C) specific orselective compounds of the invention is highly advantageous because theadministration of these compounds to mammals does not result in sedationor in significant cardivascular effects (such as changes in bloodpressure or heart rate).

The compounds are used in accordance with the invention as highlyeffective analgesics, particularly in chronic pain models, with minimalundesirable side effects, such as sedation and cardiovasculardepression, commonly seen with other agonists of the alpha₂ receptors.

In accordance with the invention the Compounds of Formula 1, includingthe novel compounds 1 through 5 may be administered at pharmaceuticallyeffective dosages. Such dosages are normally the minimum dose necessaryto achieve the desired therapeutic effect; in the treatment of chromicpain, this amount would be roughly that necessary to reduce thediscomfort caused by the pain to tolerable levels. Generally, such doseswill be in the range 1-1000 mg/day; more preferably in the range 10 to500 mg/day. However, the actual amount of the compound to beadministered in any given case will be determined by a physician takinginto account the relevant circumstances, such as the severity of thepain, the age and weight of the patient, the patient's general physicalcondition, the cause of the pain, and the route of administration.

The compounds are useful in the treatment of pain in a mammal;particularly a human being. Preferably, the patient will be given thecompound orally in any acceptable form, such as a tablet, liquid,capsule, powder and the like. However, other routes may be desirable ornecessary, particularly if the patient suffers from nausea. Such otherroutes may include, without exception, transdermal, parenteral,subcutaneous, intranasal, intrathecal, intramuscular, intravenous, andintrarectal modes of delivery. Additionally, the formulations may bedesigned to delay release of the active compound over a given period oftime, or to carefully control the amount of drug released at a giventime during the course of therapy.

Another aspect of the invention is drawn to therapeutic compositionscomprising the compounds of Formula 1, including the novel compounds 1through 5, and pharmaceutically acceptable salts of these compounds anda pharmaceutically acceptable excipient. Such an excipient may be acarrier or a diluent; this is usually mixed with the active compound, orpermitted to dilute or enclose the active compound. If a diluent, thecarrier may be solid, semi-solid, or liquid material that acts as aexcipient or vehicle for the active compound. The formulations may alsoinclude wetting agents, emulsifying agents, preserving agents,sweetening agents, and/or flavoring agents. If used in an ophthalmic orinfusion format, the formulation will usually contain one or more saltsto influence the osmotic pressure of the formulation.

It is known that chronic pain (such as pain from cancer, arthritis, andmany neuropathic injuries) and acute pain (such as that pain produced byan immediate mechanical stimulus, such as tissue section, pinch, prick,or crush) are distinct neurological phenomena mediated to a large degreeeither by different nerve fibers and neuroreceptors or by arearrangement or alteration of the function of these nerves upon chronicstimulation. Sensation of acute pain is transmitted quite quickly,primarily by afferent nerve fibers termed C fibers, which normally havea high threshold for mechanical, thermal, and chemical stimulation.While the mechanisms of chronic pain are not completely understood,acute tissue injury can give rise within minutes or hours after theinitial stimulation to secondary symptoms, including a regionalreduction in the magnitude of the stimulus necessary to elicit a painresponse. This phenomenon, which typically occurs in a region emanatingfrom (but larger than) the site of the original stimulus, is termedhyperalgesia. The secondary response can give rise to profoundlyenhanced sensitivity to mechanical or thermal stimulus.

The A afferent fibers (A∃ and A* fibers) can be stimulated at a lowerthreshold than C fibers, and appear to be involved in the sensation ofchronic pain. For example, under normal conditions, low thresholdstimulation of these fibers (such as a light brush or tickling) is notpainful. However, under certain conditions such as those following nerveinjury or in the herpes virus-mediated condition known as shingles theapplication of even such a light touch or the brush of clothing can bevery painful. This condition is termed allodynia and appears to bemediated at least in part by A afferent nerves. C fibers may also beinvolved in the sensation of chronic pain, but if so it appears clearthat persistent firing of the neurons over time brings about some sortof change which now results in the sensation of chronic pain.

By “acute pain” is meant immediate, usually high threshold, pain broughtabout by injury such as a cut, crush, burn, or by chemical stimulationsuch as that experienced upon exposure to capsaicin, the activeingredient in chili peppers.

By “chronic pain” is meant pain other than acute pain, such as, withoutlimitation, neuropathic pain, visceral pain (including that broughtabout by Crohn's disease and irritable bowel syndrome (IBS)), andreferred pain.

The following in vivo assays can be employed to demonstrate thebiological activity of the compounds of the invention.

Sedative Activity

To test sedation, six male Sprague-Dawley rats are given up to 3 mg/kgof the test compound in a saline or DMSO vehicle by intraperitonealinjection (i.p.). Sedation is graded 30 minutes following administrationof the drug by monitoring locomotor skills as follows.

The Sprague-Dawley rats are weighed and 1 ml/kg body weight of anappropriate concentration (i.e. 3 mg/ml for a final dose of 3 mg/kg)drug solution is injected intraperitoneally. Typically the test compoundis formulated in approximately 10 to 50% DMSO. The results are comparedto controls that are injected with 1 ml/kg saline or 10 to 50% DMSO. Ratactivity is then determined 30 minutes after injection of the drugsolution. Rats are placed in a dark covered chamber and a digicomanalyzer (Omnitech Electronic) quantitates their exploratory behaviorfor a five-minute period. The machine records each time the ratinterrupts an array of 32 photoelectric beams in the X and Yorientation.

Effects on Cardiovascular System

To test the effect of the compounds on the cardiovascular system,typically six cynomolgus monkeys are given 500 μg/kg of the testcompound by intravenous injection (i.v.) Or 3 mg/kg by oral gavage. Theeffects of the compound on the animals' blood pressure and heart rate ismeasured at time intervals from 30 minutes to six hours followingadministration of the drug. The peak change from a baseline measurementtaken 30 minutes before drug administration is recorded using a bloodpressure cuff modified for use on monkeys.

Specifically and typically the monkeys are weighed (approximately 4 kg)and an appropriate volume (0.1 ml/kg) of a 5 mg/ml solution of the testcompound formulated in 10 to 50% DMSO is injected into the cephalic veinin the animals' arm. Cardiovascular measurements are made with a BP 100Sautomated sphygmomanometer (Nippon Colin, Japan) at 0.5, 1, 2, 4 and 6hours.

The results of this test are expected to show that the compounds of theinvention have no or only minimal detectable effect on thecardiovascular system.

Alleviation of Acute Pain

Models to measure sensitivity to acute pain have typically involved theacute application of thermal stimuli; such a stimulus causes aprogrammed escape mechanism to remove the affected area from thestimulus. The proper stimulus is thought to involve the activation ofhigh threshold thermoreceptors and C fiber dorsal root ganglion neuronsthat transmit the pain signal to the spinal cord.

The escape response may be “wired” to occur solely through spinalneurons, which receive the afferent input from the stimulated nervereceptors and cause the “escape” neuromuscular response, or may beprocessed supraspinally—that is, at the level of the brain. A commonlyused method to measure nociceptive reflexes involves quantification ofthe withdrawal or licking of the rodent paw following thermalexcitation. See Dirig, D. M. et al., J. Neurosci. Methods 76:183-191(1997) and Hargreaves, K. et al., Pain 32:77-88 (1988), herebyincorporated by reference herein.

In a variation of this latter model, male Sprague-Dawley rats are testedby being placed on a commercially available thermal stimulus deviceconstructed as described in Hargreaves et al. This device consists of abox containing a glass plate. The nociceptive stimulus is provided by afocused projection bulb that is movable, permitting the stimulus to beapplied to the heel of one or both hindpaws of the test animal. A timeris actuated with the light source, and the response latency (defined asthe time period between application of the stimulus and an abruptwithdrawal of the hindpaw) is registered by use of a photodiode motionsensor array that turns off the timer and light. Stimulus strength canbe controlled by current regulation to the light source. Heating isautomatically terminated after 20 seconds to prevent tissue damage.

Typically four test animals per group are weighed (approximately 0.3 kg)and injected intraperitonealy (i.p.) with 1 ml/kg of the test compoundformulated in approximately 10 to 50% dimethylsulfoxide (DMSO) vehicle.Animals typically receive a 0.1 mg/kg and a 1 mg/kg dose of the threecompounds. Rats are acclimated to the test chamber for about 15 minutesprior to testing. The paw withdrawal latency is measured at 30, 60 and120 minutes after drug administration. The right and left paws aretested 1 minute apart, and the response latencies for each paw areaveraged. Stimulus intensity is sufficient to provide a temperature of45-50 degrees centigrade to each rat hindpaw.

The results in this test are expected to show that the compounds of theinvention do not provide analgesic effects in this bioassay of acutepain. Alleviation of Chronic Pain

A model in accordance with Kim and Chung 1992, Pain 150, pp 355-363(Chung model), for chronic pain (in particular peripheral neuropathy)involves the surgical ligation of the L5 (and optionally the L6) spinalnerves on one side in experimental animals. Rats recovering from thesurgery gain weight and display a level of general activity similar tothat of normal rats. However, these rats develop abnormalities of thefoot, wherein the hindpaw is moderately everted and the toes are heldtogether. More importantly, the hindpaw on the side affected by thesurgery appears to become sensitive to pain from low-thresholdmechanical stimuli, such as that producing a faint sensation of touch ina human, within about 1 week following surgery. This sensitivity tonormally non-painful touch is called “tactile allodynia” and lasts forat least two months. The response includes lifting the affected hindpawto escape from the stimulus, licking the paw and holding it in the airfor many seconds. None of these responses is normally seen in thecontrol group.

Rats are anesthetized before surgery. The surgical site is shaved andprepared either with betadine or Novacaine. Incision is made from thethoracic vertebra X111 down toward the sacrum. Muscle tissue isseparated from the spinal vertebra (left side) at the L4-S2 levels. TheL6 vertebra is located and the transverse process is carefully removedwith a small rongeur to expose the L4-L6 spinal nerves. The L5 and L6spinal nerves are isolated and tightly ligated with 6-0 silk thread. Thesame procedure is done on the right side as a control, except noligation of the spinal nerves is performed.

A complete hemostasis is confirmed, then the wounds are sutured. A smallamount of antibiotic ointment is applied to the incised area, and therat is transferred to the recovery plastic cage under a regulatedheat-temperature lamp. On the day of the experiment, at least seven daysafter the surgery, typically six rats per test group are administeredthe test drugs by intraperitoneal (i.p.) injection or oral gavage. Fori.p. injection, the compounds are formulated in d H₂O and given in avolume of 1 ml/kg body weight using an 18-gauge, 3 inch gavage needlethat is slowly inserted through the esophagus into the stomach.

Tactile allodynia is measured prior to and 30 minutes after drugadministration using von Frey hairs that are a series of fine hairs withincremental differences in stiffness. Rats are placed in a plastic cagewith a wire mesh bottom and allowed to acclimate for approximately 30minutes. The von Frey hairs are applied perpendicularly through the meshto the mid-plantar region of the rats' hindpaw with sufficient force tocause slight buckling and held for 6-8 seconds. The applied force hasbeen calculated to range from 0.41 to 15.1 grams. If the paw is sharplywithdrawn, it is considered a positive response. A normal animal willnot respond to stimuli in this range, but a surgically ligated paw willbe withdrawn in response to a 1-2 gram hair. The 50% paw withdrawalthreshold is determined using the method of Dixon, W. J., Ann. Rev.Pharmacol. Toxicol. 20:441-462 (1980) hereby incorporated by reference.The post-drug threshold is compared to the pre-drug threshold and thepercent reversal of tactile sensitivity is calculated based on a normalthreshold of 15.1 grams.

The Mouse Sulprostone Model is an alternative model in which chronicpain, allodynia can be induced in mice through intrathecal treatment ofthe animals with 200 ng sulprostone (prostaglandin E2 receptor agonist)in 50% DMSO and in volume of Sul. In this model, the pain response tostroking the flank with a paint brush is scored 8 times over a 35 minuteperiod starting 15 minutes following final administration ofsulprostone. Minami et al., 57 Pain 217-223 (1994), hereby incorporatedby reference. Sulprostone treatment alone elicits a score of 12-13 on a16-point scale.

In variants of this model, allodynia can be induced usingintraperitoneal injection of 300 μg/kg sulprostone or 30 μg/kgphenylephrine. Alternatively allodynia can be induced using intrathecalinjection of 100 ng N-methyl-D-asparate (NMDA) or 30 ng phenylephrine(PE) formulated in dH₂O in a volume of e.g. 5 microliters.

In either model, the compounds are formulated in dH₂O and given in avolume of 1 ml/kg body weight for intraperitoneal (IP) dosing.

The results of these tests are expected to illustrate that the compoundsof Formula 1, including the novel compounds 1 through 5 significantlyalleviate allodynic pain, and based on these test and/or on thecompounds ability to activate alpha_(2B) and/or alpha_(2C) adrenergicreceptors in preference over alpha_(2A) adrenergic receptors, thecompounds of the invention are expected to be useful as analgesicswithout significant side effects.

Specific Embodiments, Experimental Example A Method A: Procedure for thepreparation of 4-(2,6-dichloro-benzyl)-1,3-dihydro-imidazole-2-thione(Compound 1)

A solution of (2,6-dichloro-phenyl)-acetonitrile (Intermediate A1)(commercially available at Aldrich) (18.6 g, 100 mmol) in ethanol (40mL) and water (50 mL) was treated with KOH (30 g) and the mixture washeated to 80° C. for 20 h. The mixture was quenched with HCl until pH 3.The product was extracted with chloroform (5×50 mL). The extracts werecombined, dried over MgSO₄, filtered and evaporated to dryness. Theproduct was (2,6-dichloro-phenyl)-acetic acid, 17 g (83%). A solution of(2,6-dichloro-phenyl)-acetic acid (10 g, 49 mmol) in benzene (200 mL)was treated with oxalyl chloride (32 mL, 2M in dichloromethane) followedby a few drops of dimethyl formamide. The mixture was allowed to stirfor 3.5 h at rt. The solvent was removed under vacuum to give ˜11.5 g of(2,6-dichloro-phenyl)-acetyl chloride (Intermediate A2).

The acid chloride, Intermediate A2 (6 g, 26 8 mmol) was added viapipette to a solution of diazomethane in ether (30 mmol) (generated fromDiazald by standard Aldrich diazomethane kit) at 0° C. After 35 m, HBr(conc.) (10 mL) was added at 0° C. This was allowed to react for 35 m.The ether was removed and the mixture was neutralized with sodiumbicarbonate solution. The organic layer was removed and dried overMgSO₄. The mixture was filtered and concentrated under reduced pressureto give 1-bromo-3-(2,6-dichloro-phenyl)-propan-2-one (Intermediate A3)(˜5 g, 66%).

1-Bromo-3-(2,6-dichloro-phenyl)-propan-2-one (Intermediate A3) (˜2.5 g)was heated in formamide for 2 h at 180° C. and 150° C. for 1 additionalh. Water (50 mL) was added and the mixture was extracted with chloroform(4×50 mL). The solution was washed with brine (1×30 mL), dried overMgSO₄, filtered and evaporated to dryness. The residue was purified bychromatography on silica gel with 5% NH₃-MeOH: CH₂Cl₂ to give theproduct 5-(2,6-dichloro-benzyl)-1H-imidazole (Intermediate A4), 400 mg.

A solution of 5-(2,6-dichloro-benzyl)-1H-imidazole (Intermediate A4)(0.34 g, 1.5 mmol) in THF (6 mL) and water (6 mL) was treated withNaHCO₃ (1.2 g) at rt for 10 m. Phenyl chlorothionoformate (0.60 mL, ˜4.3mmol) was added and stirring was continued for 3 h. The mixture wasdiluted with water (10 mL) and extracted with ether (4×15 mL). Theorganic portions were combined, dried over MgSO₄, filtered and freed ofsolvent. The residue was dissolved in MeOH (6 mL) and treated with NEt₃(0.6 mL) for 18 h. The solvent was removed under vacuum and the productwas washed on a glass frit with CH₂Cl₂ to give a white solid4-(2,6-dichloro-benzyl)-1,3-dihydro-imidazole-2-thione (Compound 1) in˜50% yield.

¹H NMR (300 MHz, DMSO-d⁶): δ 12.0 (s, 1H), 11.7 (s, 1H), 7.50 (d, J=5.1Hz, 2H), 7.35 (t, J=6.0 Hz, 1H), 6.04 (s, 1H), 3.98 (s, 2H).

Example B Method B: Procedure for the preparation4-(3-chloro-2-fluoro-benzyl)-1,3-dihydro-imidazole-2-thione (Compound 2)

3-Chloro-2-fluorophenylacetonitrile (Intermediate B1) (commerciallyavailable from Matrix Scientific) (340 mg, 2 0 mmol) in ether (7 mL) andhexanes (7 mL) was cooled to 0° C. and treated with diisobutyl aluminumhydride (DIBAL, 3.0 mL, 3.0M in hexanes). After several minutes themixture was diluted with 1 M HCl and stirring was continued for 15 m.The aqueous layer was separated and extracted with ether. The organiclayers were dried over MgSO₄, filtered and evaporated to dryness. Theresidue, (3-chloro-2-fluoro-phenyl)-acetaldehyde (Intermediate B2) wasemployed in the next step without further purification.

The preparation of Intermediate B3 followed the procedure by Home et al.Heterocycles, 1994, 39, 139 incorporated herein by reference. A solutionof (3-chloro-2-fluoro-phenyl)-acetaldehyde (Intermediate B2) (0.30 g,4.57 mmol) in EtOH (7 mL) was treated with tosylmethyl isocyanide(TosMIC) (0.33 mg, 7.18 mmol) and NaCN (−10 mg, cat.). The resultingmixture was allowed to stir at rt for 20 minutes. The solvent wasremoved in vacuo and the residue was dissolved in ˜7M NH₃ in MeOH (35mL) and transferred to a re-sealable tube. This mixture was heated in are-sealable tube at 90-100° C. for 12 h. Thereafter the mixture wasconcentrated and purified by chromatography on SiO₂ with 5% MeOH (sat.w/NH₃):CH₂Cl₂ to give 5-(3-chloro-2-fluoro-benzyl)-1H-imidazole 0.4 g(31%) as an amber oil. The fumaric acid salt of the latter compound wasformed in methanol and tetrahydrofuran. The solvent was removed and thesalt was re-solvated in methanol:tetrahydrofuran and titurated with 20%ether-hexane. The solid was collected on a glass frit and dried undervacuum.

A solution of 5-(3-chloro-2-fluoro-benzyl)-1H-imidazole fumaric acidsalt (Intermediate B3) (0.24 mmol) in THF (3 mL) and water (3 mL) wastreated with NaHCO₃ (0.12 g) at rt for 10 m. Phenyl chlorothionoformate(0.11 mL, 0.6 mmol) was added and stirring was continued for 3 h. Themixture was diluted with water (10 mL) and extracted with ether (3×15mL). The organic portions were combined, dried over MgSO₄, filtered andfreed of solvent. The residue was dissolved in MeOH (5 mL) and treatedwith NEt₃ (0.3 mL) for 16 h. The solvent was removed under vacuum andthe product was washed on a glass frit with CH₂Cl₂ to give a whitesolid, 4-(3-chloro-2-fluoro-benzyl)-1,3-dihydro-imidazole-2-thione(Compound 2).

¹H NMR (300 MHz, MeOD-d⁴): δ 7.38-7.34 (m, 1H), 7.16 (t, J=3.9 Hz, 1H),7.11 (t, J=4.8

Hz, 1H) 6.53 (s, 1H), 3.87 (s, 2H).

Example C Method C: Procedure for the preparation4-(2-fluoro-benzyl)-1,3-dihydro-imidazole-2-thione (Compound 3)

A mixture of 2-fluorophenethyl alcohol (Intermediate C1) (commerciallyavailable from Aldrich) (2.8 g, 20 mmol) in CH₂Cl₂ at −10° C. wasoxidized by action of pyridinium chlorochromate: PCC (5 g, 23 mmol) inthe presence of Celite (10 g) for 1 h at −10° C. and a couple hours atrt. The mixture was filtered through silica gel and the solvent wasremoved under vacuum to give (2-fluoro-phenyl)-acetaldehyde(Intermediate C2) 2.8 g (99%).

Use of (2-fluoro-phenyl)-acetaldehyde (Intermediate C2) in theappropriate process steps of Method B (note: the fumaric acid salts werenot formed) gave a white solid4-(2-fluoro-benzyl)-1,3-dihydro-imidazole-2-thione (Compound 3) 160 mg.

¹H NMR (500 MHz, DMSO-d⁶): δ 12.0 (s, 1H), 11.7 (s, 1H), 7.30-7.14 (m,4H), 6.49 (s, 1H), 3.73 (s, 2H).

Example C-1

Use of (4-fluoro-phenyl)-acetaldehyde (commercially available fromAldrich) in the appropriate process steps of Method C gave a white solid4-(4-fluoro-benzyl)-1,3-dihydro-imidazole-2-thione (Compound 4).

¹H NMR (300 MHz, DMSO-d⁶): δ 11.9 (s, 1H), 11.7 (s, 1H), 7.30-7.10 (m,4H), 6.54 (s, 1H), 3.68 (s, 2H).

Example C-2

Use of 2-(2,4-dichloro-phenyl)-ethanol (commercially available fromAldrich) in Method C (where the Dess-Martin periodinane reagent,commercially available from Lancaster, was used in place of the PCCoxidant—procedure by Dess et al. J. Am. Chem. Soc. 1991, 113, 7277incorporated herein by reference.) produced a white solid4-(2,4-dichloro-benzyl)-1,3-dihydro-imidazole-2-thione (Compound 5).

¹H NMR (300 MHz, DMSO-d⁶): δ 12.0 (s, 1H), 11.8 (s, 1H), 7.59 (s, 1H),7.40-7.30 (m, 2H), 6.47 (s, 1H), 3.77 (s, 2H).

Example D Method D: Procedure for the preparation of2′-(2-Thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-biphenyl-4-carbonitrile(Compound 6)

4-Iodo-1-trityl-1H-imidazole (2.5 g, 5.8 mmol) (commercially availablefrom Synchem) in CH₂Cl₂ (35 mL) was cooled to 0° C. and treated withethylmagnesium bromide (1.9 mL, 3.0M in ether). After several minutesthe cooling bath was removed. The mixture was then stirred for anadditional 1 h. A solution of 2′-formyl-biphenyl-4-carbonitrile(commercially available from Oakwood) (Intermediate D1) (1.0 g, 4.8mmol) in CH₂Cl₂ (15 mL) was then added dropwise at 0° C. The flask waswarmed to rt and stirred overnight. The mixture was quenched with H₂O(50 mL) and then treated with NH₄Cl (sat. aq) (50 mL). The product wasextracted with CH₂Cl₂ (2×50 mL). The extracts were combined, dried overNa₂SO₄, filtered and concentrated to dryness. The residue was filteredthrough a pad of silica gel with 5% NH₃-MeOH: CH₂Cl₂ to give 2.5 g of2′-[hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-biphenyl-4-carbonitrile(Intermediate D2) as a white solid and used as such.

2′-[Hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-biphenyl-4-carbonitrile(Intermediate D2) (2.4 g, 4.6 mmol) in CH₂Cl₂ (100 mL) was cooled to 0°C. and treated with triethyl silane, Et₃SiH (7.4 mL, 46 mmol)(commercially available from Aldrich) followed by trifluoroacetic acid,TFA (10.7 mL, 140 mmol) dropwise. After several minutes the cooling bathwas removed and the mixture was stirred at rt for an additional 12 h.The reaction was quenched with solid NaHCO₃ followed by aqueous workup.The layers were separated and the organic layers were combined and driedover Na₂SO₄. The mixture was filtered and concentrated to dryness. Theresidue was purified by chromatography on silica gel with 3% NH₃-MeOH:CH₂Cl₂ to give the product2′-(1H-imidazol-4-ylmethyl)-biphenyl-4-carbonitrile (Intermediate D3),0.74 mg, 62% yield.

A solution of 2′-(1H-imidazol-4-ylmethyl)-biphenyl-4-carbonitrile(Intermediate D3) (0.36 g, 1.4 mmol) in THF (11 mL) and water (10 mL)was treated with NaHCO₃ (1.2 g) at rt for 5 m. Phenylchlorothionoformate (0.95 mL, 7.0 mmol) was added and stirring wascontinued for 16 h. The mixture was diluted with water (10 mL) andextracted with ether (4×15 mL). The organic portions were combined,dried over MgSO₄, filtered and freed of solvent. The residue wasdissolved in MeOH (15 mL) and treated with NEt₃ (2.0 mL) for 18 h. Thesolvent was removed under vacuum and the product was washed on a glassfrit with CH₂Cl₂ and pentane to give a solid2′-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-biphenyl-4-carbonitrile(Compound 6) in 40% yield. ¹H NMR (300 MHz, DMSO-d⁶): δ 11.8 (s, 1H),11.6 (s, 1H), 7.92 (d, J=9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.44-7.19 (m,4H), 6.14 (s, 1H), 3.63 (s, 2H).

1. A method comprising administering to a mammal a pharmaceuticalcomposition containing a therapeutically effective dose of a compoundfor the treatment of chronic pain, visceral pain, neuropathic pain,corneal pain, glaucoma, elevated intraocular pressure, ischemicneuropathies, neurodegenerative diseases, diarrhea, nasal congestion,muscle spasticity, diuresis, withdrawal syndromes, neurodegenerativediseases, optic neuropathy, spinal ischemia, stroke, memory andcognition deficits, attention deficit disorder, psychoses, manicdisorders, anxiety, depression, hypertension, congestive heart failure,cardiac ischemia, arthritis, spondylitis, gouty arthritis,osteoarthritis, juvenile arthritis, autoimmune diseases, lupuserythematosus, chronic gastrointestinal inflammations, Crohn's disease,gastritis, irritable bowel syndrome (IBS), functional dyspepsia,ulcerative colitis, or a combination thereof; said compound having astructure

where n is an integer having the values of 0 to 5; R₁ is independentlyselected from the group consisting of alkyl of 1 to 4 carbons, alkenylof 2 to 4 carbons, alkynyl of 2 to 4 carbons, (CH₂)_(m)OR₂,(CH₂)_(m)NR₃R₄, (CH₂)_(m)CN, C(O)R₅, C(O)OR₅, (CH₂)_(m)SO₂R₅, aryl,heteroaryl, F, Cl, Br, I, fluoroalkyl containing 1 to 4 carbon atoms and1 to 9 fluoro atoms, fluoroalkoxy containing 1 to 4 carbon atoms and 1to 9 fluoro atoms, N₃ and NO₂, said heteroaryl having 1 to 3 heteroatomsindependently selected from O, N and S, and said aryl and heteroarylgroups being optionally substituted with 1 to 3 radicals selected fromthe group consisting of alkyl of 1 to 4 carbons, alkenyl of 2 to 4carbons, alkynyl of 2 to 4 carbons, (CH₂)_(m)OR₂, (CH₂)_(m)NR₃R₄,(CH₂)_(m)CN, C(O)R₅, C(O)OR₅, (CH₂)_(m)SO₂R₅, fluoroalkyl containing 1to 4 carbon atoms and 1 to 9 fluoro atoms, fluoroalkoxy containing 1 to4 carbon atoms and 1 to 9 fluoro atoms, N₃ and NO₂, m is an integerhaving the values of 0, 1, 2, or 3; R₂ is H, alkyl of 1 to 4 carbons,C(O)R₅, and aryl, or heteroaryl containing 1 to 3 heteroatomsindependently selected from O, N and S, and said aryl and heteroarylgroups being optionally substituted with 1 to 3 radicals selected fromthe group consisting of alkyl of 1 to 4 carbons, alkenyl of 2 to 4carbons, alkynyl of 2 to 4 carbons, (CH₂)_(m)OR₂, (CH₂)_(m)NR₃R₄,(CH₂)_(m)CN, C(O)R₅, C(O)OR₅, (CH₂)_(m)SO₂R₅, fluoroalkyl containing 1to 4 carbon atoms and 1 to 9 fluoro atoms, fluoroalkoxy containing 1 to4 carbon atoms and 1 to 9 fluoro atoms, N₃ and NO₂; R₃ and R₄ areindependently selected from the group consisting of H, alkyl of 1 to 4carbons, C(O)R₅ and benzyl; R₅ is independently H, alkyl of 1 to 4carbons, aryl, or heteroaryl containing 1 to 3 heteroatoms independentlyselected from O, N and S, and said aryl and heteroaryl groups beingoptionally substituted with 1 to 3 radicals selected from the groupconsisting of alkyl of 1 to 4 carbons, alkenyl of 2 to 4 carbons,alkynyl of 2 to 4 carbons, (CH₂)_(m)OR₂, (CH₂)_(m)NR₃R₄, (CH₂)_(m)CN,C(O)R₅, C(O)OR₅, (CH₂)_(m)SO₂R₅, fluoroalkyl containing 1 to 4 carbonatoms and 1 to 9 fluoro atoms, fluoroalkoxy containing 1 to 4 carbonatoms and 1 to 9 fluoro atoms, N₃ and NO₂.
 2. A method in accordancewith claim 1 where the pharmaceutical composition is administered to themammal to treat pain.
 3. A method in accordance with claim 1 where thepharmaceutical composition is administered to the mammal to neuropathicpain.
 4. A method in accordance with claim 1 where the pharmaceuticalcomposition is administered to the mammal to visceral pain.
 5. A methodin accordance with claim 1 where the pharmaceutical composition isadministered orally.
 6. A method in accordance with claim 1 where thepharmaceutical composition is administered intraperitonially.
 7. Amethod in accordance with claim 1 where the compound is selected fromthe group consisting of compounds 1 through 6 shown by structuralformula below


8. A method in accordance with claim 7 where the compound has theformula


9. A method in accordance with claim 7 where the compound has theformula


10. A method in accordance with claim 7 where the compound has theformula


11. A method in accordance with claim 1 where in the formula of thecompound R₁ is independently selected from the group consisting of F,Cl, Br, CH₃, CH₂CH₃, CF₃ and CH₂OH.
 12. A method in accordance withclaim 1 where in the formula of the compound n is 1 or
 2. 13. A methodin accordance with claim 1 where in the formula of the compound m is 1.14. A method in accordance with claim 1 where in the formula of thecompound R₂ is H.
 15. A method in accordance with claim 1 where in theformula of the compound R₃ and R₄ are independently selected from H andCH₃.
 16. A method in accordance with claim 1 where in the formula of thecompound R₅ is H or CH₃.